Process for the preparation of (-)-α-(difluoromethyl)ornithine-monohydrochloride monohydrate

ABSTRACT

(±)-α-(Difluoromethyl)-ornithine is separate into its isomers using (−)-O,O′-di-p-toluoyl-L-tartaric acid. (−)-α-(Difluoromethyl)-ornithine monohydrochloride monohydrate and in particular the (−)-isomer are inhibitors of ornithine decarboxylase and thereby have numerous pharmacological actions.

This application is a 371 national stage application of PCT/EP99/07060,filed on Sep. 22, 1999, which has benefit of priority of EuropeanApplication 98117982.3, filed on Sep. 23, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for the resolution of(±)-α-difluoroniethylornithine of the formula:

using (−)-O,O′-di-p-toluoyl-L-tartaric acid.(±)-α-Difluoromethylornithine is an inhibitor of ornithine decarboxylaseand has numerous pharmacological actions (U.S. Pat. No. 4,413,141).

2. Background Art

It is known that the pharmacological activity of the (−)-isomer issignificantly greater than that of the racemate (WO-A-98/25603).

The known methods for the preparation of the (−)-isomer, however, arelaborious and unsatisfactory with respect to the yield and opticalpurity which can be achieved.

According to U.S. Pat. No. 4,413,141 or U.S. Pat. No. 4,309,442, for thepurpose of resolution, DL-3-amino-3-difluoromethyl-2-piperidone of theformula:

is used, which first has to be prepared from racemricDL-α-difluoromethylornithine monohydrochloride mono-hydrate viaformation of the methyl ester and cyclization using alkoxide. Theresolution of the piperidonie is described using classical resolvingagents such as, for example, using (+)-camphor-10-sulphonic acid orusing (+)- or (−)-binaphthyl-phosphoric acid.

BROAD DESCRIPTION OF THE INVENTION

The object of the invention consisted in developing an approach to thedesired isomer which was simpler and improved with respect to yield andoptical purity.

It has been found that (±)-α-difluoromethylornithine can be cleavedusing the commercially obtainable (−)-O,O′-di-p-toluoyl-L-tartaric acid,without circuitous routes and without having to take the disadvantagesmentioned into account, and consequently it was thus possible to achievethe object in a surprisingly simple manner.

The invention therefore relates to diastereomeric salts of (+)- or(−)-α-difluoromethylornithine of the formula:

with (−)-O,O′-di-p-toluoyl-L-tartaric acid, preferably the 1:1diastereomeric salt of (+)- or (−)-α-difluoromethylornithine with(−)-O,O′-di-p-toluoyl-L-tartaric acid and particularly preferably the1:1 diastereomeric salt of (−)-α-difluoromethylornithine with(−)-O,O′-di-p-toluoyl-L-tartaric acid.

In the preferred molar ratio of resolving agent to(−)-α-difluoromethylornithine of 1:1, in principle two free amino groupsare available for bonding. Fundamentally, both diastereomers areincluded by the invention.

A further subject of the invention is the process according to theinvention. The invention process involves resolution of(±)-α-(difluoromethyl)-ornithine of formula I. The resolution is carriedout using (−)-O,O′-di-p-toluoyl-L-tartaric acid.

DETAILED DESCRIPTION OF THE INVENTION

The resolution of (±)-α-difluoromethylornithine using(−)-O,O′-di-p-toluoyl-L-tartaric acid is expediently carried out in thepresence of a mixture of water and a water-miscible polar organicsolvent.

Suitable water-miscible polar organic solvents are, for example, loweraliphatic alcohols, such as methanol or ethanol, or acetonitrile. Apreferred water-miscible polar organic solvent is acetonitrile.

The components are expediently dissolved by heating. On cooling, as arule the desired diastereomer of (−)-α-difluoromethylornithine with(−)-O,O′-di-p-toluoyl-L-tartaric acid crystallizes out, while thediastereomer of (+)-α-difluoromethylornithine with(−)-O,O′-di-p-toluoyl-L-tartaric acid remains in solution.

Customarily, the mixture water/water-miscible polar organic solvent isselected such that the desired diastereomer of(−)-α-difluoromethylornithine with (−)-O,O′-di-p-toluoyl-L-tartaric acidcrystallizes out easily and quantitatively on cooling the solution.

Preferably, a mixture of acetonitrile/water of 0.9:1 to 1.3:1 isselected for the crystallization of the 1:1 diastereomer of(−)-α-difluoromethylornithine with (−)-O,O′-di-p-toluoyl-L-tartaricacid.

The liberation of the (−)-α-difluoromethylornithine monohydrochloridemonohydrate from the diastereomer is carried out by acidifying with amineral acid such as, with hydrochloric acid. By extraction with asuitable solvent, the (−)-α-difluoromethylornithine monohydrochloridemonohydrate can be obtained in high yield and high optical purity. The(−)-O,O′-di-p-toluoyl-L-tartaric acid can likewise be recovered fromthis extraction.

The diastereomer of (+)-α-difluoromethylornithine with(−)-di-O,O′-p-toluoyl-L-tartaric acid, which as a rule is found insolution, can likewise be analogously liberated, e.g. after evaporationof the solution, as (+)-α-difluoromethylornithine monohydrochloridemonohydrate, which can then be recovered by extraction, by acidifyingwith a mineral acid.

EXAMPLE 1 Preparation of (−)-α-difluoromethylornithine.HCl.H₂O

91 g of (±)-α-difluoromethylornithine and 19.7 g(−)-O,O′-di-p-toluoyl-L-tartaric acid were introduced into a mixture of150 ml of acetonitrile and 110 ml of water and heated to boiling, aclear solution resulting. On cooling, the diastereomeric 1:1 salt of(−)-α-difluoromethylornithine and (−)-O,O′-di-p-toluoyl-L-tartaric acidcrystallized out at 47 to 48° C. The crystallization was completed bycooling to 5° C. to 0° C. The crystallized salt was filtered off anddried. 9.7 g of white crystalline product were obtained. [α]²⁰_(D)=−99.1° (c=1 in MeOH)

¹H-NMR (400 MHz, DMSO-d₆) δ = 7.83 (d, J = 7.7 Hz, 4H) 7.30 (d, J = 7.7Hz, 4H) 6.21 (t, J = 54 Hz, 1H) 5.63 (s, 2H) 2.77 − 2.66 (m, 2H) 2.36(s, 6H) 1.87 − 1.46 (m, 4H)

M.p.: 172.9-173.7° C.

8.5 g of this salt were introduced into 100 ml of water and treated witha solution of 1.7 g of concentrated hydrochloric acid (32.2%, strength)in 20 ml of water. The suspension was extracted with 200 ml ofchloroform. The aqueous phase was evaporated to dryness. After drying at40° C. in a vacuum oven overnight, 3.2 g of white product were obtained.

[α]²⁰ _(D)=−8.8° (c=0.7 in MeOH)

EXAMPLE 2

Preparation of (+)-α-difluoromethylornithine.HCl.H₂O

From the evaporated mother liquor of the resolution from Example 1,according to the process described above, (+)-α-difluoromethylornithinemonohydrochloride monohydrate was isolated with an optical rotation of[α]²⁰ _(D)=+3.1° (c=7.0 in MeOH).

¹H-NMR (400 MHz, D₂O) δ = 6.30 (t, J = 54 Hz, 1H) 3.01 (m, 2H) 2.05 (m,1H) 1.89 (m, 1H) 1.85 (m, 1H) 1.62 (m, 1H)

What is claimed is:
 1. A salt of S-(+)- orR-(−)-α-(difluoromethyl)ornithine, the R-(−)-α-(difluoromethyl)ornithinerepresented by the formula:

and the S-(+)-α-(difluoromethyl)ornithine represented by the formula:

with (−)-O,O′-di-p-toluoyl-L-tartaric acid.
 2. 1:1 salt ofR-(−)-α-(difluoromethyl)ornithine with (−)-O,O′-di-p-toluoyl-L-tartaricacid.
 3. 1:1 salt of S-(+)-α-(difluoromethyl)ornithine with(−)-O,O′-di-p-toluoyl-L-tartaric acid.
 4. A process for the resolutionof [S-(+)/R-(−)]-α-(difluoromethyl)ornithine, theR-(−)-α-(difluoromethyl)ornithine represented by the formula:

and the S-(+)-α-(difluoromethyl)ornithine represented by the formula:

comprising conducting the resolution using(−)-O,O′-di-p-toluoyl-L-tartaric acid.
 5. The process according to claim4, wherein the process is carried out in the presence of a mixture ofwater and a water-miscible polar organic solvent.
 6. The processaccording to claim 5, wherein acetonitrile is used as the water-misciblepolar organic solvent.
 7. The process according to claim 6, whereinvolume ratio of acetonitrile to water is 0.9:1 to 1.3:1 in the mixtureof acetonitrile and water.
 8. The process according to claim 5, whereinthe water-miscible polar organic solvent is a lower aliphatic alcohol.9. The process according to claim 5, wherein acetonitrile is used as thewater-miscible polar organic solvent.
 10. The process according to claim6, wherein 1:1 salt of R-(−)-α-(difluoromethyl)ornithine with(−)-O,O′-di-p-toluoyl-L-tartaric acid is crystallized out andR-(−)-α-(difluoromethyl)ornithine monohydrochloride monohydrate isliberated by acidification.
 11. The process according to claim 10,wherein the acidification is carried out using a mineral acid.
 12. Theprocess according to claim 11, wherein the mineral acid is hydrochloricacid.
 13. The process according to claim 4, wherein 1:1 salt ofR-(−)-α-(difluoromethyl)ornithine with (−)-O,O′-di-p-toluoyl-L-tartaricacid is crystallized out and R-(−)-α-(difluoromethyl)ornithinemonohydrochloride monohydrate is liberated by acidification.
 14. Theprocess according to claim 13, wherein the acidification is carried outusing a mineral acid.
 15. The process according to claim 14, wherein themineral acid is hydrochloric acid.